eP010: Conservative management with serial biochemical monitoring for newborn screen detected Maple Syrup Urine Disease (MSUD) patients without metabolic decompensation


      Maple syrup urine disease (MSUD) is a rare inborn error of metabolism characterized by deficiency of branched-chain alpha-keto acid dehydrogenase that metabolizes the three branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. The result of this enzyme deficiency is a toxic buildup of metabolites, typically within the first 24-48 hours of life. The main neurotoxic effects are due to accumulation of large amounts of leucine which can lead to severe cerebral edema. Treatment requires immediate medical intervention to lower leucine levels. Various techniques have been used to reduce plasma leucine levels including invasive techniques such as dialysis and continuous renal replacement therapy. Risks are associated with such techniques including infections, hypovolemia, electrolyte disturbances, and fluid overload. These risks must be balanced with the risk of cerebral edema and neurologic side effect of metabolic intoxication from high leucine levels. Whatever the means, the goal remains rapid reduction in leucine levels.

      Case presentation

      We present two cases of patients with MSUD ascertained by abnormal newborn screens. Their initial leucine levels were critically elevated but showed no evidence of decompensation. They were both able to be successfully managed with conservative interventions to safely reduce leucine levels.
      Patient #1 is a 3-month-old male infant identified on newborn screen on the 5th day of life. Confirmatory testing drawn on the 6th day of life which revealed a Leucine level in the critical range of 2022 μmol/l. He was admitted to the hospital the same day for emergent management. The baby was doing well, gaining weight and neurologically intact. He was managed conservatively with a BCAA restricted formula, MSUD Anamix Early Years, intravenous fluids with D10, and NS to maintain Na greater than 137. We were able to safely reduce leucine levels by 39% within the first 24 hours and a 94% reduction within 72 hours, resulting in normalization of leucine levels to normal range of 109 μmol/l. At this time, it was indicated to add isoleucine and valine back into the diet, but the facility’s pharmacy did not stock these amino acid supplements. Therefore, we used IVA Anamix Early Years formula, which is leucine free but contained our desired isoleucine and valine. This was utilized until we received shipment of isoleucine and valine supplements. On day 4 of admission, natural protein was able to be safely reintroduced and appropriately formulated branch amino acid supplement shipments were received. He was monitored with daily plasma amino acids for a total of 7 days to ensure stability before being discharged. He continues to be routinely followed in our clinic on a weekly basis and is doing well. He is thriving with a current weight of 7.1kg and length of 61.5cm. He was molecular testing confirmed to have biallelic pathogenic missense variants in trans in the BCKDHB gene (NM_183050.4). These changes were identified as c.410C>T (p.Ala137Val) and c.1A>T (p.Met1?). He has no obvious neurologic deficits.
      Patient #2 is a 5-year-old boy also identified on newborn screen on the 4th day of life. Confirmatory labs draw on that same day revealed a leucine level of 1846 μmol/l. He had a similar course with similar results. He was managed conservatively with a leucine free diet and intravenous fluids. Also, in this case, there was a delay in shipment of supplemental isoleucine and valine, so natural protein was initiated earlier on the 3rd day of hospitalization due to a critically low valine level. While this may have slowed the rate of decline of leucine levels, we were still able to achieve a 32% reduction in leucine within the first 48 hours of hospitalization and stabilization for discharge was achieved within a week to a level of 167 μmol/l. He has since been able to receive a liver transplantation at one year of age and remains neurologically intact. Subsequent molecular testing has revealed that he carries a homozygous 213.22 kb deletion in BCKDHB gene which was consistent with the reported consanguinity of parents being second cousins.


      Advances in newborn screening and early detection has modified the disease progression in patients with MSUD. When a patient is diagnosed before metabolic decompensation, without proteolysis, the reducing of leucine can be quickly and successfully achieved without invasive measures. The success of these interventions can be assessed by clinical presentation, CMP, and frequent monitoring of plasma amino acids. As demonstrated in our patients, daily reduction is 600-750 μmol/l vs historical patients admitted with symptoms, average dropping 300-350 μmol/l. Our two patients with MSUD demonstrated the evidence that, without metabolic crisis, conservative management of high leucine levels can result in safe and timely reduction of leucine with no apparent neurologic sequela. While each case must be considered individually, these cases may change our standard approach. It may at least present an alternative approach in circumstances where continuous renal replacement therapy or a form of dialysis may not be readily available for a neonatal patient provided levels can be readily monitored to ensure an adequate decline in levels.